The goal of this proposal is to understand the role of and mechanism by which the novel adipokine, CTRP9, regulates whole body energy balance. Adipose tissue-secreted factors (collectively termed adipokines) play important roles in regulating systemic insulin sensitivity by controlling glucose and lipid utilization in the peripheral tissues. One widely studied adipokine is adiponectin, well-known for being an insulin-sensitizer that promotes fatty acid oxidation in muscles and suppresses gluconeogenesis in liver. However, adiponectin-null mice display variable and relatively mild metabolic dysfunctions, suggesting the existence of compensatory mechanisms. We have recently discovered a novel family of ten adiponectin paralogs, designated as C1q/TNF-related protein (CTRP)-1 to 10. CTRP9, the closest paralog of adiponectin, is expressed by adipose tissue and circulates in plasma as a multimeric glycoprotein. CTRP9 forms homo-oligomers as well as heterotrimers with adiponectin. Adenovirus-mediated over-expression of CTRP9 in obese (ob/ob) mice leads to a modest but significant decrease in blood glucose levels. Transgenic (Tg) mice with elevated circulating CTRP9 are significantly leaner due to reduced fat mass. When challenged with a high-fat diet, CTRP9 Tg mice are resistant to body weight gain, have significantly lower fasting glucose and insulin levels, better lipid profiles, and exhibit marked improvements in glucose tolerance tests. These in vivo phenotypes correlate with the ability of CTRP9 to suppress gluconeogenesis and promote fatty acid oxidation in vitro. Our data support the hypothesis that CTRP9 regulates body weight and adiposity by controlling glucose and fatty acid utilization in tissues. To understand the mechanism by which CTRP9 exerts its beneficial metabolic function, we aim to address the following questions: 1) what are the target tissues of CTRP9; 2) what specific metabolic processes (e.g., glucose uptake and fatty acid oxidation) are regulated by CTRP9; 3) what is the mechanism by which CTRP9 controls glucose and fatty acid utilization in vitro and in vivo; 4) what metabolic signaling pathways (e.g., Akt and/or AMPK) are activated by CTRP9 in responsive cell types; 5) what is the mechanism by which CTRP9 regulates body weight, adiposity, and insulin sensitivity in mice; and, 6) is there a possible therapeutic potential of CTRP9 in restoring insulin sensitivity and normalizing glucose and lipid profiles in a diet-induced obesity mouse model and a genetic model of obesity (as in leptin-deficient ob/ob mice)? Together, these studies will provide fundamental insights into how adipokines in general, and CTRP9 in particular, connect multiple tissues to coordinate systemic energy balance. These studies will likely provide new avenues for the treatment of obesity and diabetes.